Vegfr-fc fusion protein formulations

Abstract

Protein formulations and methods of making and using such formulations are provided herein. The formulation can be an ophthalmic formulation, such as for intravitreal administration. In some embodiments, the formulation comprises a VEGFR-Fc fusion protein, such as aflibercept.

What is claimed is: 
     
         1 . A formulation comprising:
 a) a protein;   b) a buffering agent; and   c) a stabilizer;
 wherein the formulation has a pH outside the buffering capacity of the buffering agent; 
 and the formulation is suitable for intravitreal administration. 
   
     
     
         2 . The formulation of  claim 1 , wherein the protein is a fusion protein comprising a domain of a vascular endothelial growth factor (VEGF) receptor and an Fc domain. 
     
     
         3 . The formulation of  claim 1 , wherein the buffering agent is acetate. 
     
     
         4 . The formulation of  claim 3 , wherein the acetate concentration is between 0.1 mM and 50 mM. 
     
     
         5 . The formulation of  claim 4 , wherein the acetate concentration is between 2.5 mM and 40 mM. 
     
     
         6 . The formulation of  claim 4 , wherein the acetate concentration is about 1 mM, about 2.5 mM, about 5 mM, about 10 mM, about 20 mM, about 30 mM, or about 40 mM. 
     
     
         7 . The formulation of  any of the preceding claims , wherein the pH is above 5.8. 
     
     
         8 . The formulation of  claim 7 , wherein the pH is between 5.8 and 8.5. 
     
     
         9 . The formulation of  claim 8 , wherein the pH is about 6.0, about 6.1, or about 6.2. 
     
     
         10 . The formulation of  claim 9 , wherein the pH is about 6.2. 
     
     
         11 . A formulation comprising:
 d) a protein; and   e) a stabilizer;
 wherein the formulation does not comprise a buffer; 
 and the formulation is suitable for intravitreal administration. 
   
     
     
         12 . The formulation of  claim 11 , wherein the protein is a fusion protein comprising a domain of a vascular endothelial growth factor (VEGF) receptor and an Fc domain. 
     
     
         13 . The formulation of  claim 11 or 12 , wherein the pH is between 5.0 and 7.0. 
     
     
         14 . The formulation of  claim 13 , wherein the pH is about 5.0, about 5.2, about 5.5, about 5.8, about 6.0, about 6.2, about 6.3, about 6.4, about 6.5, or about 6.8. 
     
     
         15 . The formulation of  claim 14 , wherein the pH is about 6.2. 
     
     
         16 . The formulation of  any of the preceding claims , wherein the fusion protein is aflibercept. 
     
     
         17 . The formulation of  claim 16 , wherein the concentration of aflibercept is about 40 mg/ml. 
     
     
         18 . The formulation of  any of the preceding claims , wherein the stabilizer is an amino acid or sugar. 
     
     
         19 . The formulation of  claim 18 , wherein the stabilizer is proline, glycine, arginine, sucrose, or trehalose. 
     
     
         20 . The formulation of  claim 18 , wherein the stabilizer is an amino acid and the concentration of the stabilizer is between 200 mM and 280 mM. 
     
     
         21 . The formulation of  claim 18 , wherein the concentration of the stabilizer is about  200  mM or about  280  mM. 
     
     
         22 . The formulation of  claim 18 , wherein the stabilizer is a sugar. 
     
     
         23 . The formulation of  claim 22 , wherein the sugar is sucrose. 
     
     
         24 . The formulation of  claim 22 , wherein the sugar is trehalose. 
     
     
         25 . The formulation of any one of  claims 22 to 24 , wherein the concentration of the sugar is between 2% and 10% (w/v). 
     
     
       26. The formulation of any one of  claims 22  to  24 , wherein the concentration of the sugar is about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 5%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, or about 10%. 
     
     
         27 . The formulation of  claim 22 , further comprising a second sugar. 
     
     
         28 . The formulation of  claim 27 , wherein the concentration of the sugar and the second sugar is each between 2% and 10% (w/v). 
     
     
         29 . The formulation of  claim 28 , wherein the concentration of the sugar is about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, or about 5% (w/v). 
     
     
         30 . The formulation of  claim 28 , wherein the concentration of the second sugar is about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, or about 5% (w/v). 
     
     
         31 . The formulation of  claim 28 , wherein the total concentration of the first and second sugar is about 5%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, or about 10% (w/v). 
     
     
         32 . The formulation of any one of  claims 27-31 , wherein the first sugar is sucrose and second sugar is trehalose. 
     
     
         33 . The formulation of  any of the preceding claims , further comprising a surfactant. 
     
     
         34 . The formulation of  claim 33 , wherein the surfactant is polysorbate 20, polysorbate 80 or Pluronic® F68. 
     
     
         35 . The formulation of  claim 33 , wherein the concentration of the surfactant is between 0.001 and 0.1%. 
     
     
         36 . The formulation of  claim 35 , wherein the concentration of the surfactant is about 0.01% or about 0.03%. 
     
     
         37 . The formulation of  any of the preceding claims , further comprising a tonicity agent. 
     
     
         38 . The formulation of  claim 37 , wherein the tonicity agent is sodium chloride or potassium chloride. 
     
     
         39 . The formulation of  claim 38 , wherein the concentration of the tonicity agent is between 1 mM and 150 mM. 
     
     
         40 . The formulation of  claim 39 , wherein the concentration of the tonicity agent is about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 40 mM, or about 50 mM.